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To test the hypothesis that central changes in sympathoregulation might contribute to sympathoexcitation after cyclic intermittent hypoxia (CIH) we exposed male Sprague-Dawley rats to CIH or to room air sham (Sham) for 8 hours/d for 3 weeks. After completion of the exposure we assessed heart rate, mean arterial pressure and renal sympathetic nerve activity in conscious animals before and after intracerebroventricular (i.c.v.) administration of endothelin-1 (ET-1, 3 pmol). CIHexposed animals had a significantly greater sympathetic response to ET-1 than did Sham-exposed animals (CIH 137.8 ± 15.6% of baseline; Sham 112.2 ± 10.0 % of baseline; CIH vs. Sham, P = 0.0373). This enhanced sympathetic response to i.c.v. ET-1 was associated with greater expression of endothelin receptor A (ETA) protein in the subfornical organs of CIH-exposed relative to Shamexposed rats. We conclude that 3-week CIH exposure enhances central ET-1 receptor expression and the sympathetic response to i.c.v. ET-1 suggesting central endothelin may contribute to the sympathetic and hemodynamic response to cyclic intermittent hypoxia. KeywordsIntermittent hypoxia; sympathetic nervous system; endothelin; subfornical organ; intracerebroventricular injection INTRODUCTIONPatients who develop obstructive sleep apnea (OSA) are at risk to develop an increase in arterial pressure (Hla et al.1994;Peppard et al. 2000). The pathophysiological mechanisms that connect nocturnal upper airway obstructions, with associated sleep disruption and oxygen desaturation, to diurnal hypertension remain unclear, however. Two animal models have revealed aspects of the causal link between sleep-disordered breathing and elevated arterial pressure. The first model, which closely mimics the upper airway changes of obstructive sleep apnea, established Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. that nocturnal cyclic intermittent hypoxia (CIH) rather than sleep fragmentation produced the increase in diurnal pressure. In this model, which uses a chronic dog preparation, a computer is used to activate a solenoid valve that occludes a tracheotomy tube whenever the animal sleeps (Brooks et al. 1997b). The occlusion is released when the animal awakens, mimicking human sleep apnea. Significantly, animals subjected to this protocol for 2 months developed sustained daytime elevations of arterial pressure but acoustic arousals, without desaturations, failed to change arterial pressure (Brooks et al. 1997a). NIH Public AccessThe second model represents an attempt to mimic the nocturnal fluctuations in oxygen saturation experienced by s...